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Aldehyde dehydrogenase 2 (ALDH2) is one of important factors against from the damage under oxidative stress in human body. A high proportion of East Asians carry ALDH2 inactive mutation gene. There are many diseases closely related to ALDH2, such as cardiovascular diseases, neurodegenerative diseases and liver diseases. Recent studies also have found that ALDH2 is associated with ferroptosis. Therefore, ALDH2 has becoming a potential target for the treatment of the above related diseases. Several types of small molecule activators with potential value of clinical application have been reported. The research progress on the structure and function of ALDH2 , the relationship with human diseases and its activators were summarized in this paper.
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Liver transplantation is a vital treatment for end-stage liver disease. However, the shortage of donor livers has limited the development of liver transplantation. How to expand the source of donor livers has become a challenge in the academic community. In recent years, the proportion of donors with non-alcoholic fatty liver disease (NAFLD) has been increased. Rational use of steatotic donor livers is a feasible approach to expand the donor pool. Cold ischemia injury during donor liver preservation before liver transplantation increases the risk of postoperative organ dysfunction. Therefore, it is of significance to unravel the mechanism and intervention measures of cold ischemia injury of steatotic donor livers. Cold ischemia injury of steatotic donor livers is characterized as the damage of mitochondria, lysosomes and endoplasmic reticulum at the organelle level, and up-regulated expression of adenosine monphosphate activated protein kinase (AMPK), aldehyde dehydrogenase 2 (ALDH2) and heme oxygenase (HO)-1 at the protein level. In this article, the research progresses on cold ischemia injury of steatotic donor livers and relevant intervention measures were reviewed.
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OBJECTIVE@#To investigate the correlation between aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphisms and chemotherapy-induced nausea and vomiting (CINV).@*METHODS@#A total of 90 Chinese patients with malignant tumors receiving chemotherapy for the first time were recruited in this study. The occurrence of CINV was observed within 120 h after treatment with docetaxel and cis-platinum chemotherapy (DP regimen). The data of the patients (including age, gender, tumor stage, habitual alcohol consumption, motion sickness, morning sickness, and average sleep time prior to chemotherapy) were collected through a questionnaire. ALDH2 rs671 polymorphisms of the patients were analyzed using a multiple single nucleotide polymorphism genotyping, and the Hardy-Weinberg equation was used for genetic linkage analysis. The correlations between the factors including ALDH2 rs671 polymorphisms and the occurrence of CINV were analyzed.@*RESULTS@#The incidence of CINV was 48.9% among the patients receiving their first chemotherapy with DP regimen. Univariate analysis indicated that the genetic polymorphisms of ALDH2 rs671 were significantly correlated with the occurrence of CINV (P < 0.05). Multivariate logistic analysis indicated that ALDH2 rs671 mutation (OR: 3.019, 95% CI: 1.056-8.628, P < 0.05) and average sleep time prior to chemotherapy no longer than 6 h (OR: 2.807, 95% CI: 1.033-7.628, P < 0.05) were risk factors for CINV in patients with malignant tumors receiving the first chemotherapy with DP regimen.@*CONCLUSION@#ALDH2 gene mutation at rs671 is a risk factor contributing to the occurrence of CINV, and understanding of the underlying mechanism may help to more effectively control the occurrence of CINV.
Subject(s)
Humans , Aldehyde Dehydrogenase, Mitochondrial/genetics , Antineoplastic Agents/adverse effects , Nausea/genetics , Polymorphism, Single Nucleotide , Vomiting/genetics , Neoplasms/drug therapyABSTRACT
Objective:To evaluate the effects of the alpha-lipoic acid on hepatic ischemia/reperfusion (I/R) injury and the role of (ALDH2).Methods:This experiment was performed in two parts in vivo and in vitro experiments. In vivo experiment Twenty-four male Sprague-Dawley rats, aged 8-10 weeks, weighing 250-300 g, were divided into 4 groups ( n=6 each) by the random number table method: sham operation group (Sham group), hepatic I/R group (IR group), and hepatic I/R plus α-lipoic acid group (IR+ ALA group) and hepatic I/R+ α-lipoic acid+ daidzin group (IR+ ALA+ D group). Hepatic I/R was induced by occlusion of the left and middle hepatic lobes for 60 min, followed by 6 h of reperfusion in anesthetized rats.In IR+ ALA+ D group, ALDH2 inhibitor daidzin 50 mg/kg was intraperitoneally injected at 45 min before ischemia.Alpha-lipoic acid 100 mg/kg was intraperitoneally injected at 30 min before ischemia in IR+ ALA group and IR+ ALA+ D group.Blood samples from the inferior vena cava were collected at the end of reperfusion to determine serum AST and ALT activities.Then the rats were sacrificed, and livers were removed for microscopic examination of pathological changes of the lung tissues which were scored and for determination of ALDH2 activity, level of reactive oxygen species (ROS) and expression of 4-hydroxy-trans-2-nonenal (4-HNE) and malondialdehyde (MDA) (by immuno-histochemistry). In vitro experiment Rat BRL-3A hepatocytes cultured in vitro were divided into 4 groups ( n=15 each) by the random number table method: control group (C group), hypoxia-reoxygenation group (HR group), hypoxia-reoxygenation+ α-lipoic acid group (HR+ ALA group) and hypoxia-reoxygenation+ α-lipoic acid+ daidzin group (HR+ ALA+ D group). BRL-3A hepatocytes were exposed to 95% N 2-5% CO 2 in an incubator at 37 ℃ for 6 h followed by reoxygenation with 95% O 2-5% CO 2 for 24 h. At 60 min before hypoxia, alpha-lipoic acid 100 μmol/L was addded in HR+ ALA group, and alpha-lipoic acid 100 μmol/L and daidzin 60 μmol/L were added in HR+ ALA+ D group.At 24 h of reoxygenation, cell viability was measured by CCK-8 method, ALDH2 activity was determined by spectrophotometry, ROS level was detected by DCFH-DA fluorescent probe method, and mitochondrial membrane potential (MMP) was measured by JC-1 method. Results:In vivo experiment Compared with Sham group, the serum AST and ALT activities, liver injury score, level of ROS in liver tissues and expression of 4-HNE and MDA were significantly increased ( P<0.05), and no significant change was found in ALDH2 activity in IR group ( P>0.05). Compared with IR group, the serum AST and ALT activities, liver injury score, level of ROS in liver tissues and expression of 4-HNE and MDA were significantly decreased, and the ALDH2 activity was increased in IR+ ALA group ( P<0.05). Compared with IR+ ALA group, the serum AST and ALT activities, liver injury score, level of ROS in liver tissues and expression of 4-HNE and MDA were significantly increased, and the ALDH2 activity was decreased in HR+ ALA+ D group ( P<0.05). In vitro experiment Compared with C group, the cell viability and MMP were significantly decreased, and the level of ROS was increased ( P<0.05), and no significant change was found in the activity of ALDH2 in HR group ( P>0.05). Compared with HR group, the cell viability, ALDH2 activity and MMP were significantly increased, and the level of ROS was decreased in HR+ ALA group ( P<0.05). Compared with HR+ ALA group, the cell viability, ALDH2 activity and MMP were significantly decreased, and the level of ROS was increased in HR+ ALA+ D group ( P<0.05). Conclusions:Alpha-lipoic acid can reduce hepatic I/R injury in rats, and the mechanism is related to activation of ALDH2, reduction of accumulation of toxic aldehyde and restoration of MMP.
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Objective:To evaluate the role of acetaldehyde dehydrogenase 2 (ALDH2) in hippocampus in memory decline after myocardial ischemia-reperfusion (I/R) in rats.Methods:Twenty-four healthy male Sprague-Dawley rats, aged 2-3 months, weighing 220-280 g, were divided into 3 groups ( n=8 each) using a random number table method: sham operation group (group S), myocardial I/R group (group I/R) and ALDH2 agonist ALDA-1 group (group ALDA-1). Myocardial I/R was induced by 30 min occlusion of left anterior descending branch of coronary artery followed by 120 min reperfusion in anesthetized animals.ALDA-1 10 mg/kg was intraperitoneally injected at 5 min before ischemia in group ALDA-1.The positioning navigation training in Morris water maze test was started from 6 days before developing the model.The spatial exploration in Morris water maze test was performed at 24 h after developing the model.The rats were sacrificed after the end of behavioral experiment, and the hippocampus was extracted for microscopic examination of the pathological changes (by hematoxylin and eosin staining) and for determination of the apoptosis index (AI) (by TUNEL staining), activity of ALDH2 (by colorimetry), contents of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) (by enzyme-linked immunosorbent assay), and expression of ALDH2 and 4-HNE (by Western blot). Results:Compared with group S, the number of crossing the original platform was significantly decreased, the time spent in the target quadrant was shortened, the activity of ALDH2 in the hippocampus was decreased, the expression of 4-HNE was up-regulated, and the contents of 4-HNE and MDA and AI were increased in group I/R ( P<0.05). Compared with group I/R, the number of crossing the original platform was significantly increased, the time spent in the target quadrant was prolonged, the ALDH2 activity was increased, the expression of 4-HNE was down-regulated, and the contents of 4-HNE and MDA and AI were decreased in group ALDA-1 ( P<0.05). There was no significant difference in ALDH2 expression in hippocampus among the three groups ( P>0.05). Conclusions:The mechanism of memory decline developed after myocardial I/R may be related to the decrease in ALDH2 activity and promotion of accumulation of aldehydes in the hippocampus of rats.
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Excessive drinking causes of social problems and economic loss, and has adverse physical and mental effects. If the gene polymorphism of aldehyde dehydrogenase (ALDH2), an important enzyme in the degradation of alcohol, is known, it is possible to avoid drinking alcohol to a level that exceeds its decomposition ability and prevent adverse physical and social effects. In the future, pharmacy students will contribute to improving the health of local residents as pharmacists; therefore, it is necessary for them to understand alcohol metabolism and related problems. In this study, we investigated the degree of understanding of alcohol degradation pathways, related enzymes, and polymorphisms among second- and third-year pharmacy students in their twenties before and after watching a test-linked video lecture on the subject. Third-year students (61.3 points) scored higher than second-year students (45.7 points) on average due to the learning effect. However, both the second- and third-year students did not show a high level of comprehension before the lecture. After the video lecture related to the test was shown to students, the same test was performed again. Comparing the test scores before and after the video lecture, both the second- and third-year students demonstrated a higher average score (86.1 and 93.3 points, respectively), a significant increase. From these data, it was proved that the test-linked video lecture we created could be used as an effective tool by pharmacy students to understand alcohol metabolism in a short time.
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OBJECTIVE@#To investigate the expression of aldehyde dehydrogenase 3B1 (ALDH3B1) in gastric cancer and explore its correlation with the pathological parameters and long-term prognosis of the patients.@*METHODS@#We analyzed the clinical data of 101 patients who underwent radical gastrectomy for gastric cancer in our hospital between January, 2013 and November, 2016, and examined the expression of ALDH3B1 in paraffin-embedded samples of gastric cancer tissues and adjacent tissues from these cases by immunohistochemical staining. We evaluated the correlation between ALDH3B1 expressions and histopathological parameters and assessed the predictive value of ALDH3B1 expression for long-term survival of the patients. We also examined the effect of lentivirus-mediated interference and overexpression of ALDH3B1 on the malignant behaviors of MGC-803 gastric cancer cells.@*RESULTS@#The expressions of ALDH3B1 and Ki67 were significantly higher in gastric cancer tissues than in adjacent tissues (P < 0.05). In gastric cancer patients, ALDH3B1 expression was positively correlated with peripheral blood CEA and CA19-9 levels (P < 0.01). The proportion of patients with CEA ≥5 μg/L, CA19-9 ≥37 kU/L, T stage of 3- 4, and N stage of 2-3 was significantly greater in high ALDH3B1 expression group than in low expression group. Kaplan-Meier survival analysis showed that the 5-year survival rate was significantly lower in gastric cancer patients with high ALDH3B1 expressions (P < 0.01). Univariate and Cox multiple regression analyses identified a high expression of ALDH3B1 (P < 0.05, HR= 0.231, 95% CI: 0.064-0.826), CEA≥5 μg/L (P < 0.01, HR=4.478, 95% CI: 1.530-13.110), CA19-9≥37 kU/L (P < 0.01, HR=3.877, 95% CI: 1.625-9.247), T stage of 3-4 (P < 0.01, HR=4.953, 95% CI: 1.768-13.880), and N stage of 2-3 (P < 0.05, HR=2.152, 95% CI: 1.152-4.022) as independent risk factors affecting 5-year survival after radical gastrectomy. The relative ALDH3B1 expression level, at the cut-off point of 4.66, showed a sensitivity of 76.47% and a specificity of 76% for predicting 5-year postoperative death (P < 0.01). In the cell experiment, overexpression of ALDH3B1 obviously promoted the proliferation, migration and invasion of MGC-803 cells.@*CONCLUSION@#As an independent risk factor affecting 5-year survival after radical gastrectomy, ALDH3B1 is highly expressed in gastric cancer and correlated with pathological parameters of the tumor, and a high ALDH3B1 expression may promote proliferation, invasion and metastasis of gastric cancer cells.
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Humans , Aldehyde Oxidoreductases , CA-19-9 Antigen , Carcinoembryonic Antigen , Gastrectomy , Neoplasm Staging , Prognosis , Retrospective Studies , Stomach Neoplasms/pathologyABSTRACT
Abstract: Aldehyde dehydrogenase 1 (ALDH-1) is a marker of stem cells in a variety of diseases, but its role in individuals with chronic inflammatory periapical lesions remains unknown. The aim of this study was to investigate the presence of cells with a stem cell profile based on the immunoexpression of ALDH-1 in periapical granulomas (PGs) and radicular cysts (RCs). A total of 51 cases of periapical lesions (25 PGs and 26 RCs) were subjected to immunohistochemical study. The anti-ALDH-1 antibody was applied using the immunoperoxidase technique. An immunoexpression score (intensity vs. percentage of cells) was used, with the cases being classified as low expression (score: 0 to 4) and high expression (score: 6 to 9). The Chi-square test was used with a 5% level of significance. Immunoexpression of ALDH-1 was detected in all cases of PGs and RCs. In PG cases, the expression was diffuse in connective tissue cells, with most cases exhibiting high expression (n = 18; 69.2%), while in RC cases the expression revealed focal distribution in cells of the capsule and epithelial cells of the cystic lining, with most cases classified as low expression (n = 18; 72%). Significant differences in the expression scores of ALDH-1 were observed in PGs (p = 0.003). The variable expression of ALDH-1 suggests the presence of cells with stem cell profiles in PGs and RCs. These findings suggest that periapical tissues infiltrated by chronic inflammation can recruit important cells for the repair or evolution of periapical lesions.
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@#Introduction: As the high incidence of breast cancer has a profound impact on a global scale, there is a critical need to improve the clinical outcome of the patients, including efforts to utilize bioactive natural products as treatment or preventive measures. Citral, the essential oil of lemongrass has been reported to possess cytotoxicity in breast cancer cell line . The aim of present study was to determine the capability of citral in targeting aldehyde dehydrogenase-positive (ALDH+) cells in breast cancer cells. Methods: Both MCF-7 and MDA-MB-231 cells were cultured in serum-free media to generate multicellular tumour spheroids for the evaluation of citral as an antiproliferative agent. The cells were treated with identified IC50 (50±4.30 µM and 56±3.17 µM of citral, respectively) to investigate the cytotoxicity of citral. Staining using Propidium Iodide (PI) and Hoechst 33342 was carried out to determine cell proliferation and viability. Finally, ALDH+ cells were quantified via ALDEFLUOR assay. Analysis of differences was carried out by analysis of variance (ANOVA) and independent t-test with p<0.05 considered statistically significant. Results: The size of spheroids in both cancer cell lines were reduced after treatment with the citral. PI and Hoechst 33342 staining also revealed that citral gave rise to a mixture of cells that are normal and undergoing apoptosis and necrosis. ALDEFLUOR assay analysis revealed citral significantly (p <0.05 ) inhibited the population of ALDH+ cells in MCF7 cells. Conclusion: It was demonstrated that citral reduced the ALDH+ cell population in MCF7 breast cancer spheroids by inhibiting the ALDH activity.
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A major mitochondrial enzyme for protecting cells from acetaldehyde toxicity is aldehyde dehydrogenase 2 (ALDH2). The correlation between ALDH2 dysfunction and tumorigenesis/growth/metastasis has been widely reported. Either low or high ALDH2 expression contributes to tumor progression and varies among different tumor types. Furthermore, the ALDH2∗2 polymorphism (rs671) is the most common single nucleotide polymorphism (SNP) in Asia. Epidemiological studies associate ALDH2∗2 with tumorigenesis and progression. This study summarizes the essential functions and potential ALDH2 mechanisms in the occurrence, progression, and treatment of tumors in various types of cancer. Our study indicates that ALDH2 is a potential therapeutic target for cancer therapy.
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Cancer stem cells (CSCs) are a subpopulation of cancer cells with functions similar to those of normal stem cells. Although few in number, they are capable of self-renewal, unlimited proliferation, and multi-directional differentiation potential. In addition, CSCs have the ability to escape immune surveillance. Thus, they play an important role in the occurrence and development of tumors, and they are closely related to tumor invasion, metastasis, drug resistance, and recurrence after treatment. Therefore, specific targeting of CSCs may improve the efficiency of cancer therapy. A series of corresponding promising therapeutic strategies based on CSC targeting, such as the targeting of CSC niche, CSC signaling pathways, and CSC mitochondria, are currently under development. Given the rapid progression in this field and nanotechnology, drug delivery systems (DDSs) for CSC targeting are increasingly being developed. In this review, we summarize the advances in CSC-targeted DDSs. Furthermore, we highlight the latest developmental trends through the main line of CSC occurrence and development process; some considerations about the rationale, advantages, and limitations of different DDSs for CSC-targeted therapies were discussed.
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BACKGROUND: Fragrance is one of the most important quality traits in rice, and the phenotype is attributed to the loss-of-function betaine aldehyde dehydrogenase (BADH2) gene. At least 12 allelic variations of BADH2 have been identified, and some of these have been applied to rice fragrance breeding using traditional molecular markers and Sanger sequencing techniques. However, these traditional methods have several limitations, such as being very expensive, imprecise, inefficient, and having security issues. Thus, a new molecular marker technology must be developed to improve rice fragrance breeding. RESULTS: In this study, more than 95% of the cultivated fragrant rice varieties belonged to a 7-bp deletion in exon 2 (badh2-E2) or an 8-bp deletion and 3-bp variation in exon 7 (badh2-E7). Both allelic variations resulted in the loss of function of the badh2 gene. We developed two novel SNP molecular markers, SNP_badh2-E2 and SNP_badh2- E7, related to the alleles. Their genotype and phenotype were highly cosegregated in the natural variation of rice accessions, with 160 of the 164 fragrant rice varieties detected with the two markers. These markers cosegregated with the fragrance phenotype in the F2 population. CONCLUSIONS: Two functional SNP molecular markers of badh2-E2 and badh2-E7 allelic variations were developed. These functional SNP molecular markers can be used for genotype and genetic improvement of rice fragrance through marker-assisted selection and will significantly improve the efficiency of fragrant rice breeding and promote commercial molecular breeding of rice in the future.
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Oryza/enzymology , Oryza/genetics , Betaine-Aldehyde Dehydrogenase/metabolism , Genetic Markers , Alleles , Genotyping Techniques/methods , Genotype , OdorantsABSTRACT
Microbes inhabiting the intestinal tract of humans represent a site for xenobiotic metabolism. The gut microbiome, the collection of microorganisms in the gastrointestinal tract, can alter the metabolic outcome of pharmaceuticals, environmental toxicants, and heavy metals, thereby changing their pharmacokinetics. Direct chemical modification of xenobiotics by the gut microbiome, either through the intestinal tract or re-entering the gut enterohepatic circulation, can lead to increased metabolism or bioactivation, depending on the enzymatic activity within the microbial niche. Unique enzymes encoded within the microbiome include those that reverse the modifications imparted by host detoxification pathways. Additionally, the microbiome can limit xenobiotic absorption in the small intestine by increasing the expression of cell-cell adhesion proteins, supporting the protective mucosal layer, and/or directly sequestering chemicals. Lastly, host gene expression is regulated by the microbiome, including CYP450s, multi-drug resistance proteins, and the transcription factors that regulate them. While the microbiome affects the host and pharmacokinetics of the xenobiotic, xenobiotics can also influence the viability and metabolism of the microbiome. Our understanding of the complex interconnectedness between host, microbiome, and metabolism will advance with new modeling systems, technology development and refinement, and mechanistic studies focused on the contribution of human and microbial metabolism.
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The present study attempts to study alcohol metabolizing and antioxidant properties of Gynostemma pentaphyllum(Thunb.) Makino distillate (GPD) and combination effects with Hovenia dulcis Thunb. extract (HDE) on these activities.The alcohol-metabolizing activity of GPD with/without HDE was determined by assessing alcohol dehydrogenase(ADH) and acetaldehyde dehydrogenase (ALDH) activities. To define the effect of GPD with/without HDE on alcoholmetabolism, antioxidant activities and total phenolic content of GPD with/without HD extract were evaluated using2-diphenyl-1-picrylhydrazyl free radical scavenging, ferrous chelating assays, and the Folin–Ciocalteu method.Cytotoxicity against human normal liver CHANG cells was also evaluated using the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. GPD treatment alone or in combination with HDE significantly increased ADHand ALDH activities; combined treatment was most effective. Total phenolic and flavonoid contents were greater incombination than the level found in GPD alone. GPD revealed a synergistic antioxidant effect when combined withHDE. GPD and/or HDE had no antiproliferative activity against the normal liver cell line. These results suggest thatGPD-HDE combination is the possible natural resource for the management of alcohol-induced liver injury.
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With the rapid development of organ transplantation in China,the donation after cardiac death (DCD) donor organs are widely used.However,the quality of these organs is relatively poor,so the way to preserve and maintain organ still remains a severe problem.Among them,ischemic reperfusion injury (IRI) impairs the organs severely.Acetaldehyde dehydrogenase 2 (ALDH2) protects organs from stress conditions,including ischemia-reperfusion injury,and the activation and autophagy inhibition also protects the organs from stress conditions as well.Recent studies showed that ALDH2 can regulate autophagy to inhibit the organ injury during ischemia-reperfusion.Our study aims to discuss the new findings in this mechanism.
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Alcohol-induced flushing syndrome is one of the alcohol hypersensitivity reactions commonly found among Asian population. This study was designed to find markers that can predict this particular propensity among Korean population and to assess the applicability of this finding to build a prediction model as forensic DNA phenotyping tool to operate in practical forensic cases. Five hundred seventy unrelated Koreans were genotyped using microfluidic technology with 24 possible candidate single nucleotide polymorphism (SNP) markers. Of the 24 candidate SNPs, four markers, rs671, rs2074356, rs4646776, and rs10849915, on chromosome 12 showed statistically significant association with P-values ranging from 1.39×10⁻¹⁴ to 0.004988 among our subjects. All four markers show relatively high specificity values, ranging from 0.804651 to 0.972093, presenting their capabilities as differential SNPs that can distinguish a person with or without alcohol-induced flushing syndrome. Maneuvering these candidate SNPs as well as finding additional potential markers through future studies will help building an appropriate prediction model for Koreans that can be used as supplementary tool for individual identification.
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Humans , Alcohols , Aldehyde Dehydrogenase , Asian People , Chromosomes, Human, Pair 12 , DNA , Flushing , Hypersensitivity , Microfluidics , Polymorphism, Single Nucleotide , Sensitivity and SpecificityABSTRACT
Obesity is increasing in an alarming rate worldwide, which causes higher risks of some diseases, such as type 2 diabetes, cardiovascular diseases, and cancer. Current therapeutic approaches, either pancreatic lipase inhibitors or appetite suppressors, are generally of limited effectiveness. Brown adipose tissue (BAT) and beige cells dissipate fatty acids as heat to maintain body temperature, termed non-shivering thermogenesis; the activity and mass of BAT and beige cells are negatively correlated with overweight and obesity. The existence of BAT and beige cells in human adults provides an effective weight reduction therapy, a process likely to be amenable to pharmacological intervention. Herein, we combed through the physiology of thermogenesis and the role of BAT and beige cells in combating with obesity. We summarized the thermogenic regulators identified in the past decades, targeting G protein-coupled receptors, transient receptor potential channels, nuclear receptors and miscellaneous pathways. Advances in clinical trials were also presented. The main purpose of this review is to provide a comprehensive and up-to-date knowledge from the biological importance of thermogenesis in energy homeostasis to the representative thermogenic regulators for treating obesity. Thermogenic regulators might have a large potential for further investigations to be developed as lead compounds in fighting obesity.
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Managing the dysregulated host response to infection remains a major challenge in sepsis care. Chinese treatment guideline recommends adding XueBiJing, a five-herb medicine, to antibiotic-based sepsis care. Although adding XueBiJing further reduced 28-day mortality modulating the host response, pharmacokinetic herb-drug interaction is a widely recognized issue that needs to be studied. Building on our earlier systematic chemical and human pharmacokinetic investigations of XueBiJing, we evaluated the degree of pharmacokinetic compatibility for XueBiJing/antibiotic combination based on mechanistic evidence of interaction risk. Considering both XueBiJing‒antibiotic and antibiotic‒XueBiJing interaction potential, we integrated informatics-based approach with experimental approach and developed a compound pair-based method for data processing. To reflect clinical reality, we selected for study XueBiJing compounds bioavailable for drug interactions and 45 antibiotics commonly used in sepsis care in China. Based on the data of interacting with drug metabolizing enzymes and transporters, no XueBiJing compound could pair, as perpetrator, with the antibiotics. Although some antibiotics could, due to their inhibition of uridine 5'-diphosphoglucuronosyltransferase 2B15, organic anion transporters 1/2 and/or organic anion-transporting polypeptide 1B3, pair with senkyunolide I, tanshinol and salvianolic acid B, the potential interactions (resulting in increased exposure) are likely desirable due to these XueBiJing compounds' low baseline exposure levels. Inhibition of aldehyde dehydrogenase by 7 antibiotics probably results in undesirable reduction of exposure to protocatechuic acid from XueBiJing. Collectively, XueBiJing/antibiotic combination exhibited a high degree of pharmacokinetic compatibility at clinically relevant doses. The methodology developed can be applied to investigate other drug combinations.
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PURPOSE: The activity of mammary stem cells (MaSCs) is essential to mammary growth, differentiation and regeneration in cycles of pregnancy, lactation, and involution. The capability to recruit the mammary gland through the cycles is attributed to stem cells. It was shown that the intraductal (i.duc) injection of pegylated liposomal doxorubicin (PLD) to multiparous FVB/N mice was associated with a significantly reduced outgrowth potential of mammary gland cells. We have explored i.duc PLD's effect on stem cell number and function in mouse mammary gland and aldehyde dehydrogenase (ALDH)'s availability as a mouse MaSC marker.METHODS: The total mammary epithelium was purified from 6 to 8-month-old FVB/N control and i.duc PLD-administered mice treated twice and analyzed by flow cytometry and limiting dilution cleared mammary fat pad transplants.RESULTS: There was no significant difference in the proportions of stem cell-enriched population (CD49(fhigh)CD24(med)) between control and i.duc PLD-treated groups. However, we found a significant reduction in the outgrowth potential of CD49(fhigh)CD24(med) and CD49(fhigh)CD24(med)ALDH(+) cells from i.duc PLD-treated mammary glands. We discovered that adding ALDH to CD49(fhigh)CD24(med) had the possibility of better marker selection for MaSC of mice.CONCLUSION: We present i.duc administration of PLD to reduce MaSC function, but not the number; and ALDH activity may add further selection of MaSCs to CD49f CD24 in mouse mammary glands. Screening of chemotherapeutic drugs or other natural products by this method of stem cell analysis may provide safe i.duc treatment in breast cancer.
Subject(s)
Animals , Female , Humans , Infant , Mice , Pregnancy , Adipose Tissue , Aldehyde Dehydrogenase , Biological Products , Breast Neoplasms , Doxorubicin , Epithelial Cells , Epithelium , Flow Cytometry , Lactation , Mammary Glands, Human , Mass Screening , Methods , Regeneration , Stem CellsABSTRACT
Objective To investigate the expression of aldehyde dehydrogenase 1 (ALDH1) and human epidermal growth factor receptor (HER-2) in human gastric cancer tissues, and analyze its relationship with clinicopathological characteristics. Methods The surgical specimens, gastroscopic biopsy specimens and clinicopathological data of 162 patients with gastric cancer treated in Hengshui People's Hospital Affiliated to Hebei Medical University from July 2015 to March 2018 were selected. The expressions of ALDH1 and HER-2 protein in gastric cancer tissues and paracancerous tissues of 162 patients were detected by immunohistochemistry. The relationship between the results and clinicopathological characteristics were analyzed. Results ALDH1 and HER-2 protein were significantly higher in gastric cancer tissues (48.7%, 34.0%) than those in paracancerous tissues (8.0%, 11.7%, P<0.05). The expression of ALDH1 protein was significantly related to T state, histological differentiation, TNM stage, lymph node metastasis and distant metastasis (P<0.05), but had no relationship with gender, age and tumor location. The expression of HER-2 protein was significantly related to T state, tumor location, histological differentiation, TNM stage and distant metastasis (P<0.05), but had no relationship with gender, age and lymph node metastasis. ALDH1 expression was positively associated with HER-2 (P<0.00). Conclusions ALDH1 and HER-2 are upregulated in gastric cancer. ALDH1 and HER-2 may promote the development of gastric cancer and serve as new therapeutic targets for gastric cancer.